Insulin discharge is being investigated in normal and diabetic subjects and in patients with increased peripheral resistance to the actions of insulin, such as obese subjects and patients with acromegaly and Cushing's disease. This is mainly being done with a newly developed "staircase" type glucose infusion which permits characterization of the discharge from the early and late insulin release compartments of the beta cell. L-leucine has also been of use, being a stimulant to which pancreatic beta cells of obese and acromegalic patients are particularly responsive. In addition to characterizing stimulatory patterns in diabetic and obese patients, their sensitivity to an inhibitor of insulin release, diphenylhydantoin is being studied in detecting deficiencies in insulin reserve. We plan to continue the use of insulin inhibitors in studying the defective insulin secretion of the diabetic beta cell, and apply them to further studies of alpha cell dysfunction in diabetes, as well as in the therapy of insulinomas. Studies in progress to further characterize the role of glucagon hypersecretion in the pathophysiological manifestations of diabetes mellitus as well as in its pathogenesis.